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Numéro de publicationUS6225078 B1
Type de publicationOctroi
Numéro de demandeUS 09/122,591
Date de publication1 mai 2001
Date de dépôt27 juil. 1998
Date de priorité29 juil. 1997
État de paiement des fraisPayé
Autre référence de publicationCN1095991C, CN1224159A, DE69822949D1, DE69822949T2, EP0901018A2, EP0901018A3, EP0901018B1
Numéro de publication09122591, 122591, US 6225078 B1, US 6225078B1, US-B1-6225078, US6225078 B1, US6225078B1
InventeursShin Ikeda, Toshihiko Yoshioka, Shiro Nankai
Cessionnaire d'origineMatsushita Electric Industrial Co., Ltd.
Exporter la citationBiBTeX, EndNote, RefMan
Liens externes: USPTO, Cession USPTO, Espacenet
Method for quantitative measurement of a substrate
US 6225078 B1
Résumé
The invention provides a method for quantitative measurement of a substrate with high accuracy by electrochemically oxidizing an electron mediator which has been reduced by enzyme reaction thereby determining the substrate concentration based on a current flowing during electrochemical oxidation from which adverse effects of an easy-to-oxidize substance on the oxidation process have been minimized. The quantitating method in accordance with the present invention comprises a first step for causing a substrate contained in a sample to react with a specific oxidoreductase to the substrate in the presence of an electron mediator in oxidized state, and a second step for electrochemically reducing the electron mediator in oxidized state which remains non-reduced by the enzyme reaction in the first step, thereby obtaining a current flowing during electrochemical reduction.
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Revendications(6)
What is claimed is:
1. A method for quantitative measurement of a substrate in a sample solution without interference from the presence of an easily oxidizable substance with a biosensor comprising an electrically insulating base plate, an electrode system having at least a working electrode and a counter electrode formed on said base plate, and a reaction layer including an oxidoreductase and an electron mediator in oxidized state disposed on said electrode system, said method comprising the steps of:
contacting the sample solution with said reaction layer to react the substrate with said oxidoreductase to produce reduced oxidoreductase, wherein said reduced oxidoreductase reacts with said electron mediator to cause a reduction of at least some of said electron mediator, wherein reduced and
unreduced electron mediator are obtained,
applying a voltage between the working electrode and the counter electrode to electrochemically reduce said unreduced electron mediator at the working electrode, and measuring a reduction current flowing between the working electrode and the counter electrode, thereby quantifying the substrate.
2. The method for quantitative measurement of a substrate in a sample solution in accordance with claim 1, wherein said electrode system further comprises a reference electrode.
3. The method for quantitative measurement of a substrate in a sample solution in accordance with claim 2, wherein said reaction layer further includes a hydrophilic polymer.
4. The method for quantitative measurement of a substrate in a sample solution in accordance with claim 2, wherein said reaction layer further includes additional electron mediator in reduced state to measure low concentrations of the substrate.
5. The method for quantitative measurement of a substrate in a sample solution in accordance with claim 1, wherein said reaction layer further includes a hydrophilic polymer.
6. The method for quantitative measurement of a substrate in a sample solution in accordance with claim 1, wherein said reaction layer further includes additional electron mediator in reduced state to measure low concentrations of the substrate.
Description
BACKGROUND OF THE INVENTION

The present invention relates to a method for rapid and easy quantitative measurement of a substrate contained in a sample such as blood, urine and fruit juice with high accuracy.

A conventional simple method for quantitating a specific component in a sample solution with no dilution or agitation of the sample solution is to cause the specific component to react with an oxidoreductase whose substrate corresponds to the specific component in the presence of an electron mediator or electron acceptor, followed by electrochemical oxidation of the electron mediator which has been reduced by this enzyme reaction, thereby to determine the oxidation current flowing during this electrochemical oxidation.

This method normally uses a biosensor as disclosed in the Japanese Laid-Open Patent Publication Hei 3-202764.

The biosensor is produced by first forming an electrode system having a working electrode and a counter electrode on an electrically insulating base plate by a screen printing method or the like, subsequently forming a reaction layer including an oxidoreductase and an electron mediator above the electrode system, and finally bonding a cover and a spacer to the electrically insulating base plate.

With this biosensor, various specific components can be quantitated by varying the oxidoreductase.

Here, a glucose sensor will be described as an example of biosensor.

Conventionally known method for quantitative measurement of glucose is a system comprising a combination of glucose oxidase with an oxygen electrode or a hydrogen peroxide electrode (e.g., “Biosensor”, ed. by Shuichi Suzuki, Kodansha, Japan).

Glucose oxidase selectively oxidizes a substrate β-D-glucose to D-glucono-δ-lactone by utilizing oxygen dissolved in a sample solution as an electron mediator. When the substrate is oxidized by the glucose oxidase, the oxygen used as the electron mediator is reduced to hydrogen peroxide. The glucose concentration can be quantitated either by measurement of the volume of oxygen consumed during this reaction using an oxygen electrode or by measurement of the volume of hydrogen peroxide produced using a hydrogen peroxide electrode of platinum or the like.

However, this method has a drawback that the measurement is largely affected by the concentration of oxygen contained in a sample solution, depending on the measuring object. This system has another drawback that the system cannot function in the absence of oxygen.

To overcome these problems, a type of glucose sensor has been developed which includes an organic compound or a metal complex such as potassium ferricyanide, ferrocene derivatives, quinone derivatives, etc. as electron mediator, in place of oxygen.

This biosensor can carry a known amount of glucose oxidase on an electrode system, together with an electron mediator in their stabilized state. As a result, the electrode system can be integrated with the reaction layer almost in dry state.

Such biosensor is normally disposable and facilitates measurement of the concentration of glucose by a simple instillation of a measuring sample at a sensor chip mounted in a measurement device. Therefore, this biosensor has been attracting much attention recently.

As described above, the substrate in a sample can be quantitated based on the current flowing across the electrodes during oxidation of the electron mediator which has been reduced by a series of enzyme reaction.

If the oxidation current value is measured with a two-electrode system comprising a working electrode and a counter electrode, then the presence of an electron mediator in oxidized state which must be reduced on the counter electrode becomes mandatory.

When the measuring sample is predicted to have a low concentration of substrate, it becomes unnecessary to secure the presence of such electron mediator in oxidized state, because the amount of oxidized electron mediator to be reduced by enzyme reaction is small.

However, when the measuring sample is predicted to have a high concentration of substrate, most of the electron mediator in oxidized state is reduced by enzyme reaction, resulting in a deficiency of oxidized electron mediator which can be reduced on the counter electrode. This renders the reduction on the counter electrode to show a rate-determining step, affecting the resultant current value.

Moreover, depending on sample, an easy-to-oxidize substance may be present that is oxidized to induce an oxidation current at the same time when the electron mediator in reduced state is oxidized on the electrode, producing a positive error in the current value measured. Furthermore, a high concentration of substrate may vary the oxidation current value.

BRIEF SUMMARY OF THE INVENTION

The object of the present invention is therefore to provide a method for high accuracy quantitative measurement of a substrate in a wide range of substrate concentration, particularly in high substrate concentrations by suppressing the effect on the current value of a deficiency of electron mediator in oxidized state to be reduced on the counter electrode and minimizing adverse effects of an easy-to-oxidize substance on the current value.

The present invention provides a method for quantitative measurement of a substrate comprising:

a first step for causing a substrate contained in a sample to react with a specific oxidoreductase to the substrate in the presence of an electron mediator in oxidized state, and

a second step for electrochemically reducing the electron mediator in oxidized state which remains non-reduced by the enzyme reaction in the first step, thereby obtaining a current flowing during the electrochemical reduction.

While the novel features of the invention are set forth particularly in the appended claims, the invention, both as to organization and content, will be better understood and appreciated, along with other objects and features thereof, from the following detailed description taken in conjunction with the drawings.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

FIG. 1 is an exploded perspective view of a two-electrode system glucose sensor with an omission of the reaction layer in one example to which the present invention has been applied.

FIG. 2 is an exploded perspective view of a three-electrode system glucose sensor with an omission of the reaction layer in one example to which the present invention has been applied.

FIG. 3 is a longitudinal cross-sectional view of the vital part of the same glucose sensor from which the spacer and the cover have been omitted.

FIG. 4 illustrates the characteristics of the response of a two-electrode system glucose sensor to various glucose standard solutions in one example to which the present invention has been applied.

FIG. 5 illustrates the characteristics of the response of a two-electrode system glucose sensor to various glucose standard solutions in another example to which the present invention has been applied.

FIG. 6 illustrates the characteristics of the response of a three-electrode system glucose sensor to various glucose standard solutions in another example to which the present invention has been applied.

DETAILED DESCRIPTION OF THE INVENTION

The easy-to-oxidize substances include ascorbic acid and uric acid contained in blood. Such substances resist electrochemical reduction and would not generate reduction current.

Therefore, by the method where the substrate concentration is quantitated by reducing electron mediator in oxidized state which remains non-reduced by a series of enzyme reaction and reading the resultant reduction current flowing during the reduction process, the adverse effect of the easy-to-oxidize substance can be minimized, thereby realizing higher accuracy quantitation of a substrate.

From the aspect of the oxidation-reduction occurring on the electrodes, if the two-electrode system is applied for measurement of the reduction current value, the oxidation of the electron mediator in reduced state shows the rate-determining step due to a small volume of electron mediator which has been reduced by the enzyme reaction if the substrate concentration is low. The reduction current value, therefore, increases with the increases in the substrate concentration.

Since the electron mediator in oxidized state decreases as the concentration of the substrate increases, the electron mediator in oxidized state becomes deficient at a certain concentration of substrate. Therefore, in the oxidation-reduction occurring on the electrodes, the reduction of the electron mediator in oxidized state shows the rate-determining step, manifesting decreased reduction current value.

The reduction current value during this process is an exact reflection of the amount of electron mediator in oxidized state which failed to be reduced by the enzyme reaction, thus demonstrating exceptional response characteristics to the concentration of substrate.

Even at low substrate concentrations, it is preferred that an electron mediator in reduced state is added to the enzyme reaction system where the substrate is reacted with an enzyme (oxidoreductase) in the presence of an electron mediator in oxidized state, in order to render the reduction of the electron mediator in oxidized state to show the rate-determining step. Participation of electron mediator in reduced state in the enzyme reaction system facilitates high accuracy quantitation of a substrate in a wider range of substrate concentrations.

The method for measurement of the reduction current value includes the two-electrode system having a working electrode and a counter electrode and a three-electrode system further having a reference electrode. The latter permits more accurate quantitative measurement of a substrate at higher concentrations.

Application of the method for quantitative measurement of a substrate in accordance with the present invention to a biosensor comprising an electrode system having at least a working electrode and a counter electrode formed on an electrically insulating base plate, and a reaction layer formed on the electrode system and including at least an oxidoreductase realizes high accuracy quantitation of a specific component contained in a body sample and thus preferable.

Further inclusion of a hydrophilic polymer in the reaction layer is preferable because it is helpful for preventing adsorption of protein or the like in the sample onto the surface of the electrode system.

Coating of the surface of the reaction layer with a layer containing lipid helps smooth supply of a sample to the reaction layer. This lipid coating may be applied if occasion demands.

A pH buffer may further be included in the reaction layer in order to increase the enzyme activity in the reaction layer.

Applicable oxidoreductase may be exemplified as glucose oxidase, glucose dehydrogenase, lactate oxidase, lactate dehydrogenase, uricase, fructose dehydrogenase, alcohol oxidase, cholesterol oxidase, xanthine oxidase, amino acid oxidase and the like.

A combination of plural oxidoreductases may also be used, such as glucose oxidase plus invertase, glucose oxidase plus invertase plus mutarotase, fructose dehydrogenase plus invertase, or the like.

As the electron mediator, potassium ferricyanide, p-benzoquinone, phenazine methosulfate, methylene blue, ferrocene derivatives, or the like may be used. The use of oxygen for electron mediator can yield a similar sensor response. Those electron mediators are used singly or in combination (a combination of two or more).

Applicable hydrophilic polymer may be exemplified as carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin and its derivative, a polymer of acrylic acid or an acrylate, a polymer of methacrylic acid or a methacrylate, starch and its derivative, a polymer of maleic anhydride or a maleate, cellulose derivatives such as hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, carboxymethylethyl cellulose or the like, polyamino acid such as polylysine, and polystyrene sulfonate.

Among them, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose and carboxymethylethyl cellulose are preferred. Polyamino acid such as polylysine, polyvinyl alcohol and polystyrene sulfonate may also be used preferably.

As the lipid, any amphipathic phospholipid such as lecithin, phosphatidylcholine, phosphatidylethanolamine or the like may be used preferably.

The pH buffer may be exemplified as potassium dihydrogen phosphate-dipotassium phosphate, potassium dihydrogen phosphate-disodium phosphate, sodium dihydrogen phosphate-dipotassium phosphate, sodium dihydrogen phosphate-disodium phosphate, citric acid-disodium phosphate, citric acid-dipotassium phosphate, citric acid-trisodium citrate, citric acid-tripotassium citrate, potassium dihydrogen citrate-sodium hydroxide, sodium dihydrogen citrate-sodium hydroxide, sodium hydrogen maleate-sodium hydroxide, potassium hydrogen phthalate-sodium hydroxide, succinic acid-sodium tetraborate, maleic acid-tris(hydroxymethyl)aminomethane, tris(hydroxymethyl)aminomethane-tris(hydroxymethyl)aminomethane hydrochloride, [N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid]-sodium hydroxide, [N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid]-sodium hydroxide, [piperazine-N,N′-bis(2-ethanesulfonic acid)]-sodium hydroxide and the like.

Those enzymes and electron mediators may be dissolved in a sample solution or otherwise isolated from the sample solution by fixing the enzyme layer containing those constituents to the base plate so as to avoid their direct dissolution in the sample solution. If the latter configuration is selected, it is preferable for the reaction layer to further include a hydrophilic polymer.

In the following, the present invention will be described more specifically referring to concrete embodiments.

FIG. 1 shows an exploded perspective view of a two-electrode system glucose sensor with an omission of the reaction layer. A silver paste is printed on an electrically insulating base plate 1 of polyethylene terephthalate by the screen printing method so as to form leads 2 and 3 on the base plate 1. Subsequently, a conductive carbon paste containing a resin binder is printed on the base plate 1 so as to form a working electrode 4. The working electrode 4 is in contact with the lead 2. Then, an electrically insulating layer 6 is further formed on the base plate 1 by printing thereon an insulating paste. The electrically insulating layer 6 covers the periphery of the working electrode 4 so as to hold the exposed area of the working electrode 4 constant. Thereafter, a conductive carbon paste containing a resin binder is printed on the base plate 1 so as to cause the carbon paste to contact the previously formed lead 3, which formed a ring-like counter electrode 5.

Then, the electrically insulating base plate 1, a cover 9 having an air vent 11 and a spacer 10 are bonded to each other in a positional relationship as shown by the dotted chain line in FIG. 1, which gives a biosensor used as a glucose sensor. The spacer 10 has a slit 13 for forming a sample supply path between the base plate and the cover. Numeral 12 corresponds to an opening of the sample supply path.

FIG. 2 shows an exploded perspective view of a three-electrode system glucose sensor with an omission of the reaction layer. This glucose sensor has the same configuration as that of FIG. 1, except that the glucose sensor further comprises a reference electrode 15 made of a carbon paste formed outside the periphery of the counter electrode 5 so as to be exposed from the electrically insulating layer 6, and a lead 14 for the reference electrode.

FIG. 3 is a longitudinal cross-sectional view showing the vital part of a biosensor used in one example for application of the present invention, with an omission of the spacer and the cover.

A reaction layer 7 including an enzyme and an electron mediator is formed on the electrically insulating base plate 1 above which the electrode system has been formed as shown in FIG. 1, and a lecithin layer 8 is further formed on the reaction layer 7.

EXAMPLE 1

In this example, the reaction layer was formed by dropping a mixed aqueous solution of glucose oxidase (EC1.1.3.4; hereinafter referred to as “GOD”) with potassium ferricyanide on the electrode system formed on the base plate 1 in FIG. 1 and drying it. Then, the lecithin layer was formed by dropping a toluene solution of lecithin on the reaction layer and drying it.

The cover 9 and the spacer 10 were then bonded to the base plate 1 in a positional relationship shown by the dotted line in FIG. 1, which gave a glucose sensor used in this example.

Glucose standard solutions at various concentrations were then formulated as sample solutions. Each of those aqueous glucose standard solutions (3 μl) was supplied to the glucose sensor from the opening 12 of the sample supply path. The sample solution advanced to the air vent 11 and dissolved the reaction layer 7 and the lecithin layer above the electrode system. Upon dissolution of the reaction layer 7, enzyme reaction where glucose contained in the sample solution is oxidized to gluconolactone by the GOD will take place. This enzyme reaction accompanies at the same time reduction of the potassium ferricyanide to potassium ferrocyanide to produce ferrocyanide ions.

When a certain time had lapsed after supply of the sample solution, a voltage of −1.0 V was applied to the working electrode with reference to the counter electrode 5, which induced reduction of the potassium ferricyanide on the working electrode and oxidation of the potassium ferrocyanide on the counter electrode to generate a current flow across the electrodes. The current flowing during this oxidation-reduction was read 5 seconds after application of the voltage.

FIG. 4 shows the sensor responses to the various aqueous glucose standard solutions by defining the current value at a glucose concentration of about 700 mg/dl as 100%.

The sensor response showed linear increases with the increases in the glucose concentrations in a range of 0 to 700 mg/dl. This suggests the rate-determining step of the oxidation of the potassium ferrocyanide on the counter electrode due to small amounts of ferrocyanide ions produced by the enzyme reaction.

The sensor response decreased as the glucose concentrations increased above 700 mg/dl. This indicates the rate-determining step of the reduction of the ferricyanide ions on the working electrode because of sufficiently large amounts of the ferrocyanide ions produced by the enzyme reaction.

As is evident from FIG. 4, the sensor showed excellent response characteristics irrespective of the glucose (substrate) concentrations.

EXAMPLE 2

In this example, an aqueous solution of carboxymethyl cellulose (hereinafter referred to as “CMC”) was dropped on the electrode system above the base plate 1 in FIG. 1 and dried to form a CMC layer. Then, the reaction layer and the lecithin layer were formed in the same manner as in Example 1. The presence of the CMC layer minimizes the adverse effect on the measurement by adsorption of protein onto the surface of the electrodes.

A glucose sensor was produced in the same manner as in Example 1 and evaluated for its responses to various aqueous glucose standard solutions as formulated in Example 1. The sensor showed similar response characteristics to those of Example 1, with less variations.

EXAMPLE 3

In this example, the CMC layer was formed similarly by dropping an aqueous CMC solution on the electrode system above the base plate 1 in FIG. 1 and drying it. Then, a mixed aqueous solution of GOD, potassium ferricyanide and potassium ferrocyanide was dropped on the CMC layer and dried to form the reaction layer. A glucose sensor was produced in the same manner as in Example 1 and evaluated for its responses to various aqueous glucose standard solutions as formulated in Example 1.

FIG. 5 summarizes the sensor responses to the various aqueous glucose standard solutions by defining the responsive current value to a solution including 0 mg/dl glucose as 100%.

As is seen from FIG. 5, the sensor response decreased as the glucose concentrations increased. The reason is that because potassium ferrocyanide coexisted in the reaction layer, the ferrocyanide ions to be oxidized on the counter electrode were always secured sufficiently, which ensured the rate-determining step of the reduction of ferricyanide ions on the working electrode even if the concentration of the substrate is low.

The sensor showed excellent response characteristics irrespective of the glucose (substrate) concentrations.

EXAMPLE 4

In this example, the CMC layer was formed by dropping an aqueous CMC solution on the electrode system above the electrically insulating base plate 1 in FIG. 2, while avoiding the reference electrode 15, and drying it. Then, a mixed aqueous solution of GOD and potassium ferricyanide was dropped on the CMC layer and dried to form the reaction layer, above which a toluene solution of lecithin was dropped and dried to form thereon the lecithin layer.

Then, the cover 9 and the spacer 10 were bonded to the base plate 1 in a positional relationship shown by the dotted chain line in FIG. 2, which gave a glucose sensor used in this example.

Each of the various aqueous glucose standard solutions (3 μl) formulated in Example 1 was supplied from the opening 12 of the sample supply path. When a certain time lapsed after supply of the sample solution, a voltage was applied onto the working electrode at a potential of −0.8 V using the reference electrode 15 as standard. And, 5 seconds after the voltage application, the current flowing across the working electrode 4 and the counter electrode 5 was measured.

FIG. 6 summarizes the sensor responses to the various aqueous glucose standard solutions by defining the responsive current value to a solution including 0 mg/dl glucose as 100%.

As shown in FIG. 6, the sensor showed excellent response characteristics in a wide range of glucose (substrate) concentrations, permitting quantitation up to 6,000 mg/dl or so.

EXAMPLE 5

A glucose sensor was produced in the same manner as in Example 4.

Then, the sensor was evaluated for its responses in the same manner as in Example 4 except for the use of various aqueous glucose standard solutions formulated in Example 1 further containing known amounts of ascorbic acid as sample solutions.

The sensor showed substantially identical responses to those of the glucose sensor in Example 4 despite the presence of ascorbic acid, thus demonstrating excellent response characteristics.

In the foregoing examples, although conductive carbon paste and insulating paste were used to form printed patterns, the present invention is not limited to those.

As discussed above, according to the present invention, the concentration of a substrate can be quantitated with high accuracy in a wide range of substrate concentrations, particularly in high substrate concentrations.

Although the present invention has been described in terms of the presently preferred embodiments, it is to be understood that such disclosure is not to be interpreted as limiting. Various alterations and modifications will no doubt become apparent to those skilled in the art to which the present invention pertains, after having read the above disclosure. Accordingly, it is intended that the appended claims be interpreted as covering all alterations and modifications as fall within the true spirit and scope of the invention.

Citations de brevets
Brevet cité Date de dépôt Date de publication Déposant Titre
US388604511 mai 197327 mai 1975Meiattini FrancoProcess for the enzymatic determination of glucose with a glucose-oxidase/peroxidase enzyme system
US5288636 *14 déc. 199022 févr. 1994Boehringer Mannheim CorporationEnzyme electrode system
US537833214 avr. 19933 janv. 1995The United States Of America As Represented By The Secretary Of CommerceAmperometric flow injection analysis biosensor for glucose based on graphite paste modified with tetracyanoquinodimethane
US5582697 *20 avr. 199510 déc. 1996Matsushita Electric Industrial Co., Ltd.Biosensor, and a method and a device for quantifying a substrate in a sample liquid using the same
US5650062 *12 sept. 199522 juil. 1997Matsushita Electric Industrial Co., Ltd.Biosensor, and a method and a device for quantifying a substrate in a sample liquid using the same
US5658443 *19 juil. 199419 août 1997Matsushita Electric Industrial Co., Ltd.Biosensor and method for producing the same
US5863400 *12 avr. 199526 janv. 1999Usf Filtration & Separations Group Inc.Electrochemical cells
EP0732406A1 *10 juil. 199518 sept. 1996Matsushita Electric Industrial Co., Ltd.A method and a device for quantifying a substrate in a sample liquid using a biosensor
JPH03202764A * Titre non disponible
WO1984003562A1 *6 mars 198413 sept. 1984Matsushita Electric Ind Co LtdBiosensor
WO1995000662A121 juin 19945 janv. 1995Boehringer Mannheim CorporationDiagnostic reagent stabilizer
Citations hors brevets
Référence
1 *Simultaneous Use of Dehydrogenases and Hexacyanoferrate(III) Ion in Electrochemical Biosensors for L-Lactate, D-Lactate and L-Glutamate Ions, Analytica Chimica Acta 278:25-33, 1993.
Référencé par
Brevet citant Date de dépôt Date de publication Déposant Titre
US6808619 *17 mai 200126 oct. 2004Roche Diagnostics Operations, Inc.Electrode system
US753458316 mai 200319 mai 2009Oxford Biosencors LimitedAnalyte measurement
US764537318 juin 200412 janv. 2010Roche Diagnostic Operations, Inc.System and method for coding information on a biosensor test strip
US764542118 juin 200412 janv. 2010Roche Diagnostics Operations, Inc.System and method for coding information on a biosensor test strip
US764846831 déc. 200219 janv. 2010Pelikon Technologies, Inc.Method and apparatus for penetrating tissue
US766614928 oct. 200223 févr. 2010Peliken Technologies, Inc.Cassette of lancet cartridges for sampling blood
US767423231 déc. 20029 mars 2010Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US768231812 juin 200223 mars 2010Pelikan Technologies, Inc.Blood sampling apparatus and method
US769979112 juin 200220 avr. 2010Pelikan Technologies, Inc.Method and apparatus for improving success rate of blood yield from a fingerstick
US770870118 déc. 20024 mai 2010Pelikan Technologies, Inc.Method and apparatus for a multi-use body fluid sampling device
US771321418 déc. 200211 mai 2010Pelikan Technologies, Inc.Method and apparatus for a multi-use body fluid sampling device with optical analyte sensing
US771786331 déc. 200218 mai 2010Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US771843918 juin 200418 mai 2010Roche Diagnostics Operations, Inc.System and method for coding information on a biosensor test strip
US772746718 juin 20041 juin 2010Roche Diagnostics Operations, Inc.Reagent stripe for test strip
US773172913 févr. 20078 juin 2010Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US774917412 juin 20026 juil. 2010Pelikan Technologies, Inc.Method and apparatus for lancet launching device intergrated onto a blood-sampling cartridge
US774943718 juin 20046 juil. 2010Roche Diagnostics Operations, Inc.Method and reagent for producing narrow, homogenous reagent stripes
US77806316 nov. 200124 août 2010Pelikan Technologies, Inc.Apparatus and method for penetration with shaft having a sensor for sensing penetration depth
US780704322 févr. 20055 oct. 2010Oakville Hong Kong Company LimitedMicrofluidic test device
US78224543 janv. 200526 oct. 2010Pelikan Technologies, Inc.Fluid sampling device with improved analyte detecting member configuration
US782902318 juin 20049 nov. 2010Roche Diagnostics Operations, Inc.Test strip with vent opening
US783317113 févr. 200716 nov. 2010Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US78506217 juin 200414 déc. 2010Pelikan Technologies, Inc.Method and apparatus for body fluid sampling and analyte sensing
US785062222 déc. 200514 déc. 2010Pelikan Technologies, Inc.Tissue penetration device
US786252020 juin 20084 janv. 2011Pelikan Technologies, Inc.Body fluid sampling module with a continuous compression tissue interface surface
US787499416 oct. 200625 janv. 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US787504725 janv. 200725 janv. 2011Pelikan Technologies, Inc.Method and apparatus for a multi-use body fluid sampling device with sterility barrier release
US787961829 janv. 20091 févr. 2011Roche Diagnostics Operations, Inc.Method and reagent for producing narrow, homogenous reagent strips
US78921833 juil. 200322 févr. 2011Pelikan Technologies, Inc.Method and apparatus for body fluid sampling and analyte sensing
US789218530 sept. 200822 févr. 2011Pelikan Technologies, Inc.Method and apparatus for body fluid sampling and analyte sensing
US789284920 févr. 200922 févr. 2011Roche Diagnostics Operations, Inc.Reagent stripe for test strip
US790136231 déc. 20028 mars 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US790136521 mars 20078 mars 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US790977526 juin 200722 mars 2011Pelikan Technologies, Inc.Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge
US790977729 sept. 200622 mars 2011Pelikan Technologies, IncMethod and apparatus for penetrating tissue
US790977820 avr. 200722 mars 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US79144658 févr. 200729 mars 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US793878729 sept. 200610 mai 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US797647616 mars 200712 juil. 2011Pelikan Technologies, Inc.Device and method for variable speed lancet
US79771129 déc. 200812 juil. 2011Roche Diagnostics Operations, Inc.System and method for determining an abused sensor during analyte measurement
US798105522 déc. 200519 juil. 2011Pelikan Technologies, Inc.Tissue penetration device
US798105618 juin 200719 juil. 2011Pelikan Technologies, Inc.Methods and apparatus for lancet actuation
US798864421 mars 20072 août 2011Pelikan Technologies, Inc.Method and apparatus for a multi-use body fluid sampling device with sterility barrier release
US79886453 mai 20072 août 2011Pelikan Technologies, Inc.Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties
US800744619 oct. 200630 août 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US801677422 déc. 200513 sept. 2011Pelikan Technologies, Inc.Tissue penetration device
US805807718 juin 200415 nov. 2011Roche Diagnostics Operations, Inc.Method for coding information on a biosensor test strip
US806223111 oct. 200622 nov. 2011Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US807103018 juin 20046 déc. 2011Roche Diagnostics Operations, Inc.Test strip with flared sample receiving chamber
US80713847 oct. 20086 déc. 2011Roche Diagnostics Operations, Inc.Control and calibration solutions and methods for their use
US807996010 oct. 200620 déc. 2011Pelikan Technologies, Inc.Methods and apparatus for lancet actuation
US808399317 déc. 200927 déc. 2011Riche Diagnostics Operations, Inc.System and method for coding information on a biosensor test strip
US809266815 juin 200910 janv. 2012Roche Diagnostics Operations, Inc.System and method for quality assurance of a biosensor test strip
US811941415 sept. 201021 févr. 2012Roche Diagnostics Operations, Inc.Test strip with slot vent opening
US812370026 juin 200728 févr. 2012Pelikan Technologies, Inc.Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge
US814272123 sept. 201027 mars 2012Roche Diagnostics Operations, Inc.Test strip with slot vent opening
US814816430 déc. 20093 avr. 2012Roche Diagnostics Operations, Inc.System and method for determining the concentration of an analyte in a sample fluid
US815774810 janv. 200817 avr. 2012Pelikan Technologies, Inc.Methods and apparatus for lancet actuation
US819742116 juil. 200712 juin 2012Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US819742314 déc. 201012 juin 2012Pelikan Technologies, Inc.Method and apparatus for penetrating tissue
US820223123 avr. 200719 juin 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US820631722 déc. 200526 juin 2012Sanofi-Aventis Deutschland GmbhTissue penetration device
US820631926 août 201026 juin 2012Sanofi-Aventis Deutschland GmbhTissue penetration device
US820656518 juin 200426 juin 2012Roche Diagnostics Operation, Inc.System and method for coding information on a biosensor test strip
US821103722 déc. 20053 juil. 2012Pelikan Technologies, Inc.Tissue penetration device
US821137920 sept. 20113 juil. 2012Roche Diagnostics Operations, Inc.Test strip with slot vent opening
US821615423 déc. 200510 juil. 2012Sanofi-Aventis Deutschland GmbhTissue penetration device
US822133422 déc. 201017 juil. 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US822204416 nov. 201117 juil. 2012Roche Diagnostics Operations, Inc.Test strip with flared sample receiving chamber
US823591518 déc. 20087 août 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US825192110 juin 201028 août 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for body fluid sampling and analyte sensing
US82626141 juin 200411 sept. 2012Pelikan Technologies, Inc.Method and apparatus for fluid injection
US826787030 mai 200318 sept. 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for body fluid sampling with hybrid actuation
US828257629 sept. 20049 oct. 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for an improved sample capture device
US828257715 juin 20079 oct. 2012Sanofi-Aventis Deutschland GmbhMethod and apparatus for lancet launching device integrated onto a blood-sampling cartridge
US828770325 sept. 200816 oct. 2012Roche Diagnostics Operations, Inc.Biosensor and method of making
US829353824 févr. 201023 oct. 2012Roche Diagnostics Operations, Inc.System and method for coding information on a biosensor test strip
US829691823 août 201030 oct. 2012Sanofi-Aventis Deutschland GmbhMethod of manufacturing a fluid sampling device with improved analyte detecting member configuration
US829882813 mars 201230 oct. 2012Roche Diagnostics Operations, Inc.System and method for determining the concentration of an analyte in a sample fluid
US833742116 déc. 200825 déc. 2012Sanofi-Aventis Deutschland GmbhTissue penetration device
US836099123 déc. 200529 janv. 2013Sanofi-Aventis Deutschland GmbhTissue penetration device
US836099225 nov. 200829 janv. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US83666373 déc. 20085 févr. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US837201630 sept. 200812 févr. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for body fluid sampling and analyte sensing
US83826826 févr. 200726 févr. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US83826837 mars 201226 févr. 2013Sanofi-Aventis Deutschland GmbhTissue penetration device
US838855127 mai 20085 mars 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for multi-use body fluid sampling device with sterility barrier release
US84038641 mai 200626 mars 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US840410011 sept. 200626 mars 2013Bayer Healthcare LlcGated voltammetry
US841450316 mars 20079 avr. 2013Sanofi-Aventis Deutschland GmbhMethods and apparatus for lancet actuation
US842575719 déc. 200723 avr. 2013Bayer Healthcare LlcGated amperometry
US843082826 janv. 200730 avr. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for a multi-use body fluid sampling device with sterility barrier release
US843519019 janv. 20077 mai 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US843987226 avr. 201014 mai 2013Sanofi-Aventis Deutschland GmbhApparatus and method for penetration with shaft having a sensor for sensing penetration depth
US849150016 avr. 200723 juil. 2013Sanofi-Aventis Deutschland GmbhMethods and apparatus for lancet actuation
US849660116 avr. 200730 juil. 2013Sanofi-Aventis Deutschland GmbhMethods and apparatus for lancet actuation
US850728916 juil. 201213 août 2013Roche Diagnostics Operations, Inc.System and method for coding information on a biosensor test strip
US855130825 sept. 20088 oct. 2013Roche Diagnostics Operations, Inc.Biosensor and method of making
US855682927 janv. 200915 oct. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US856254516 déc. 200822 oct. 2013Sanofi-Aventis Deutschland GmbhTissue penetration device
US857489530 déc. 20035 nov. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus using optical techniques to measure analyte levels
US85798316 oct. 200612 nov. 2013Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US858637324 oct. 201219 nov. 2013Roche Diagnostics Operations, Inc.System and method for determining the concentration of an analyte in a sample fluid
US862293018 juil. 20117 janv. 2014Sanofi-Aventis Deutschland GmbhTissue penetration device
US86366731 déc. 200828 janv. 2014Sanofi-Aventis Deutschland GmbhTissue penetration device
US864164327 avr. 20064 févr. 2014Sanofi-Aventis Deutschland GmbhSampling module device and method
US864164423 avr. 20084 févr. 2014Sanofi-Aventis Deutschland GmbhBlood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
US864748928 févr. 201311 févr. 2014Bayer Healthcare LlcGated voltammetry devices
US865283126 mars 200818 févr. 2014Sanofi-Aventis Deutschland GmbhMethod and apparatus for analyte measurement test time
US866344220 oct. 20084 mars 2014Roche Diagnostics Operations, Inc.System and method for analyte measurement using dose sufficiency electrodes
US866865631 déc. 200411 mars 2014Sanofi-Aventis Deutschland GmbhMethod and apparatus for improving fluidic flow and sample capture
US867903316 juin 201125 mars 2014Sanofi-Aventis Deutschland GmbhTissue penetration device
US86798533 juil. 200725 mars 2014Roche Diagnostics Operations, Inc.Biosensor with laser-sealed capillary space and method of making
US869079629 sept. 20068 avr. 2014Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US870262429 janv. 201022 avr. 2014Sanofi-Aventis Deutschland GmbhAnalyte measurement device with a single shot actuator
US87216716 juil. 200513 mai 2014Sanofi-Aventis Deutschland GmbhElectric lancet actuator
US878433525 juil. 200822 juil. 2014Sanofi-Aventis Deutschland GmbhBody fluid sampling device with a capacitive sensor
US880820115 janv. 200819 août 2014Sanofi-Aventis Deutschland GmbhMethods and apparatus for penetrating tissue
US882820320 mai 20059 sept. 2014Sanofi-Aventis Deutschland GmbhPrintable hydrogels for biosensors
US88455492 déc. 200830 sept. 2014Sanofi-Aventis Deutschland GmbhMethod for penetrating tissue
US88455503 déc. 201230 sept. 2014Sanofi-Aventis Deutschland GmbhTissue penetration device
US88592932 juin 201114 oct. 2014Roche Diagnostics Operations, Inc.Method for determining whether a disposable, dry regent, electrochemical test strip is unsuitable for use
US887703528 mars 20134 nov. 2014Bayer Healthcare LlcGated amperometry methods
US890594529 mars 20129 déc. 2014Dominique M. FreemanMethod and apparatus for penetrating tissue
US894591019 juin 20123 févr. 2015Sanofi-Aventis Deutschland GmbhMethod and apparatus for an improved sample capture device
US896547618 avr. 201124 févr. 2015Sanofi-Aventis Deutschland GmbhTissue penetration device
US903463926 juin 201219 mai 2015Sanofi-Aventis Deutschland GmbhMethod and apparatus using optical techniques to measure analyte levels
US907284231 juil. 20137 juil. 2015Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US908929416 janv. 201428 juil. 2015Sanofi-Aventis Deutschland GmbhAnalyte measurement device with a single shot actuator
US908967821 mai 201228 juil. 2015Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US911001320 déc. 201318 août 2015Bayer Healthcare LlcGated voltammetry methods
US914440112 déc. 200529 sept. 2015Sanofi-Aventis Deutschland GmbhLow pain penetrating member
US918646814 janv. 201417 nov. 2015Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US92266999 nov. 20105 janv. 2016Sanofi-Aventis Deutschland GmbhBody fluid sampling module with a continuous compression tissue interface surface
US924826718 juil. 20132 févr. 2016Sanofi-Aventis Deustchland GmbhTissue penetration device
US92614761 avr. 201416 févr. 2016Sanofi SaPrintable hydrogel for biosensors
US931419411 janv. 200719 avr. 2016Sanofi-Aventis Deutschland GmbhTissue penetration device
US933961216 déc. 200817 mai 2016Sanofi-Aventis Deutschland GmbhTissue penetration device
US935168014 oct. 200431 mai 2016Sanofi-Aventis Deutschland GmbhMethod and apparatus for a variable user interface
US937516929 janv. 201028 juin 2016Sanofi-Aventis Deutschland GmbhCam drive for managing disposable penetrating member actions with a single motor and motor and control system
US938694410 avr. 200912 juil. 2016Sanofi-Aventis Deutschland GmbhMethod and apparatus for analyte detecting device
US941091514 juil. 20149 août 2016Roche Operations Ltd.System and method for quality assurance of a biosensor test strip
US941091728 févr. 20149 août 2016Ascensia Diabetes Care Holdings AgMethod of using a biosensor
US942753229 sept. 201430 août 2016Sanofi-Aventis Deutschland GmbhTissue penetration device
US949816029 sept. 201422 nov. 2016Sanofi-Aventis Deutschland GmbhMethod for penetrating tissue
US956099320 déc. 20137 févr. 2017Sanofi-Aventis Deutschland GmbhBlood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
US956100010 déc. 20137 févr. 2017Sanofi-Aventis Deutschland GmbhMethod and apparatus for improving fluidic flow and sample capture
US96941443 déc. 20134 juil. 2017Sanofi-Aventis Deutschland GmbhSampling module device and method
US97240218 déc. 20148 août 2017Sanofi-Aventis Deutschland GmbhMethod and apparatus for penetrating tissue
US20030232369 *17 avr. 200318 déc. 2003Bushnell David A.Molecular structure of RNA polymerase II
US20050164329 *16 mai 200328 juil. 2005Wallace-Davis Emma N.K.Analyte measurement
US20050230252 *22 févr. 200520 oct. 2005Tsai Fu HMicrofluidic test device
US20070219573 *20 avr. 200720 sept. 2007Dominique FreemanMethod and apparatus for penetrating tissue
WO2008050943A1 *21 juin 20072 mai 2008Pusan National University Industry-University Cooperation FoundationNanocatalyst-based biosensor
Classifications
Classification aux États-Unis205/777.5, 205/778, 204/403.15, 435/14, 204/403.11, 204/403.08, 435/25
Classification internationaleC12Q1/00, G01N27/327, C12Q1/26
Classification coopérativeC12Q1/004, C12Q1/006
Classification européenneC12Q1/00B6B, C12Q1/00B4
Événements juridiques
DateCodeÉvénementDescription
27 juil. 1998ASAssignment
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